Pudendal nerve injury impairs anorectal function and health related quality of life measures ≥2 years after 3D conformal radiotherapy for prostate cancer.

PURPOSE: To compare GI symptoms, measures of generic and disease specific health related quality of life (HRQoL), anorectal and pudendal nerve function and anal sphincter morphology between (i) patients ≥2 years after 3D conformal radiotherapy (3D-CRT)±high dose rate (HDR) brachytherapy for carcinoma of the prostate and aged matched patients before radiotherapy and (ii) symptomatic and asymptomatic patients ≥2 years after 3D-CRT ± HDR brachytherapy. MATERIAL AND METHODS: Methodology included: (i) modified LENT-SOMA scales for GI symptoms, (ii) EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires for generic and disease specific HRQoL, (iii) anorectal manometry and terminal motor latency for anorectal and pudendal nerve function and (iv) endorectal ultrasound for anal sphincter morphology. GI symptoms, parameters of HRQoL, anorectal and pudendal nerve function and anal sphincter morphology were compared using Mann-Whitney's U, unpaired t and χ2 tests. RESULTS: Impairment of HRQoL bowel symptoms in the patients ≥2 years after 3D-CRT ± HDR brachytherapy was associated with worse anorectal motor and sensory function, internal and external anal sphincter morphology and 5× greater prevalence of pudendal nerve dysfunction compared with age matched patients before radiotherapy. Symptomatic patients had worse (i) HRQoL measures including global quality of life and bowel and urinary symptom scores, (ii) rectal bleeding, fecal urgency and incontinence scores and (iii) a 2× higher prevalence of pudendal nerve dysfunction compared with asymptomatic patients. Rectal and anal (i) V 40 Gy >65%, (ii) Dmax >60 Gy, (iii) pudendal nerve Dmax >60 Gy and (iv) Anal V 60 Gy >40% were associated with a greater prevalence of pudendal nerve dysfunction. CONCLUSIONS: 3D-CRT ± HDR brachytherapy for prostate carcinoma, impairs late functional measures including HRQoL, anorectal and pudendal nerve function. Rectal, anal and pudendal nerve radiation dose constraints are proposed for reducing the prevalence of pudendal nerve dysfunction.

Pudendal nerve injury in men with fecal incontinence after radiotherapy for prostate cancer.

BACKGROUND: The precise etiology of fecal incontinence (FI), which occurs frequently following external beam radiotherapy (EBRT) for prostate carcinoma is unknown. It is possibly related to pelvic nerve injury. The aim of this study was to assess the incidence of pudendal nerve dysfunction in men with FI after EBRT for prostate cancer compared to men with FI but no history of EBRT. MATERIAL AND METHODS: Data were evaluated from 74 men with intact anal sphincters on endo-anal ultrasound (17 post-EBRT) who had been investigated for FI at a tertiary center. Wexner incontinence scores, pudendal nerve function, anorectal manometry, and rectal sensitivity were compared between the two patient groups. RESULTS: Post-radiotherapy patients were older (77±6 vs. 62±17 years, p<0.005) and had worse incontinence than those with no history of radiotherapy (Wexner score; 13±3 vs. 8±4; p<0.005). Bilateral pudendal nerve terminal motor latency (PNTML) was abnormal in 87% of radiotherapy versus 22% of non-radiotherapy patients (p<0.001) and the significant difference persisted even after correction for age differences. Anal sphincter pressures and rectal sensitivity for both groups were similar. CONCLUSION: There is a markedly higher incidence of pudendal nerve dysfunction in men with FI after EBRT for prostate cancer compared with men with FI from other etiologies. The increased severity of incontinence in radiotherapy patients is not matched by alterations in either anal sphincter pressures or rectal sensitivity compared to FI in non-ERBT patients.

Radiation Therapy and Indigenous Peoples in Canada and Australia: Building Paths Toward Reconciliation in Cancer Care Delivery.

Indigenous peoples represent approximately 5% of the world's population and reside in over 90 countries worldwide. They embody a rich diversity of cultures, traditions, languages and relationships with the land that are shared through many generations and that are distinct from those of the settler societies within which they now live. Many Indigenous peoples have a shared experience of discrimination, trauma, and violation of rights, rooted in complex sociopolitical relationships with settler societies that are still ongoing. This results in continuing social injustices and pronounced disparities in health for many Indigenous peoples around the globe. Indigenous peoples exhibit a significantly higher cancer incidence, mortality, and poorer survival compared to non-Indigenous peoples. Cancer services, including radiotherapy, have not been designed to support the specific values and needs of Indigenous populations, resulting in poorer access to cancer services for Indigenous peoples globally across the entire cancer care spectrum. Specific to radiotherapy, available evidence demonstrates disparities in radiotherapy uptake between Indigenous and non-Indigenous patients. Radiotherapy centres are also located disparately further away from Indigenous communities. Studies are limited by a lack of Indigenous-specific data to help inform effective radiotherapy delivery. Recent Indigenous-led partnerships and initiatives have helped to address existing gaps in cancer care, and radiation oncologists play an important role in supporting such efforts. In this article, we present an overview of access to radiotherapy for Indigenous peoples in Canada and Australia, with a focus on strengthening cancer care delivery through education, partnerships, and research.

Comparative gene expression analysis of NKT cell subpopulations.

Natural killer T (NKT) cells are a lymphocyte lineage, which has diverse immune regulatory activities in many disease settings. Most previous studies have investigated the functions of this family of cells as a single entity, but more recent evidence highlights the distinct functional and phenotypic properties of NKT cell subpopulations. It is likely that the diverse functions of NKT cells are regulated and coordinated by these different NKT subsets. Little is known about how NKT subsets differ in their interactions with the host. We have undertaken the first microarray analysis comparing the gene expression profiles of activated human NKT cell subpopulations, including CD8(+) NKT cells, which have often been overlooked. We describe the significant gene expression differences among NKT cell subpopulations and some of the molecules likely to confer their distinct functional roles. Several genes not associated previously with NKT cells were shown to be expressed differentially in specific NKT cell subpopulations. Our findings provide new insights into the NKT cell family, which may direct further research toward better manipulation of NKT cells for therapeutic applications.

Bone morphogenetic protein 4 contributes to the maintenance of primitive cord blood hematopoietic progenitors in an ex vivo stroma-noncontact co-culture system.

Establishment of conditions supporting hematopoietic stem cell (HSC) maintenance and expansion ex vivo is critical for wider clinical application of cord blood (CB) transplantation. AFT024 is a murine fetal liver cell line that expands primitive hematopoietic cells via a process that is not understood. Here we show that bone morphogenic protein 4 (BMP4) is produced by AFT024 and contributes significantly to the maintenance of co-cultured CB-derived primitive cells. Significant amounts of BMP4 mRNA are produced by the supportive AFT024 stromal cell line, and secreted BMP4 protein accumulates in AFT024 conditioned medium. Blockade of BMP4 activity in this coculture model using neutralizing BMP4 monoclonal antibody reduced expansion of primitive CB cells on the basis of phenotypic (CD34(+)CD38(-)) and functional criteria [long-term culture initiating cells (LTC-IC)] and significantly reduced the capacity of the cultured CB stem cells to support repopulation in the nonobese diabetic-severe combined immunodeficiency (NOD-SCID) xenograft model. Therefore, BMP4 is a key growth factor for maintenance of HSC and contributes to the unique properties of the AFT024 stromal noncontact culture.

Treatment of spinal cord compression: are we overusing radiotherapy alone compared to surgery and radiotherapy?

INTRODUCTION: This article describes how patients with metastatic spinal cord compression (MSCC) were treated from 2005 to 2011 at a single institution. A comparison is made with an international and standardized scoring system which would have predicted which patients would have a better outcome with neurosurgery in addition to radiotherapy in accordance with current best practice standards. METHOD: A retrospective audit of all MSCC patients presenting from 2005 to 2011 was undertaken. An assessment of outcome was made by using ambulatory assessment tool and by comparing overall survival with published standards. RESULTS: In all, 39 patients were identified, of whom 37 received radiotherapy alone and two (5%) received surgery and postoperative radiotherapy. The international standardized scoring system predicted 28 (72%) of the 39 patients might have had a better outcome with neurosurgery in addition to radiotherapy. MSCC patients generally had reasonable outcomes, but selected patients could potentially do better with decompressive surgery. CONCLUSION: There is a subset of MSCC patients who have poor predicted ambulatory rates after radiotherapy alone and who may benefit from decompressive surgery. It is recommended that MSCC patients be categorized according to the international scoring system to identify appropriate candidates for surgical intervention and postoperative radiotherapy or radiotherapy alone.

Development of CD4+CD25+FoxP3+ regulatory T cells from cord blood hematopoietic progenitor cells.

Adult stem cells are capable of generating all of the cells of the hematopoietic system, and this process is orchestrated in part by the interactions between these cells and the stroma. T cell progenitors emerge from the stem cell compartment and migrate to the thymus, where their terminal differentiation and maturation occur, and it is during this phase that selection shapes the immune repertoire. Notch ligands, including Delta-like 1 (DL1), play a critical role in this lymphoid differentiation. To mimic this in vitro, stroma-expressing DL1 have been used to generate CD4(+)CD8(+) double-positive and single-positive T cells from hematopoietic stem/progenitor cells. This system provides a robust tool to investigate thymopoiesis; however, its capacity to generate regulatory T cells (Tregs) has yet to be reported. Natural Tregs (nTregs) develop in the thymus and help maintain immune homeostasis and have potential clinical use as a cell therapy for modulation of autoimmune disease or for transplant tolerization. Here, we describe for the first time the development of a population of CD4(+)CD25(+) CD127(lo)FoxP3(+) cells that emerge in coculture of cord blood (CB) CD34(+) progenitors on OP9-DL1 stroma. These hematopoietic progenitor-derived CD4(+)CD25(+) Tregs have comparable suppressor function with CB nTregs in vitro. The addition of IL-2 to the coculture enhanced the expansion and survival of this population significantly. This manipulable culture system, therefore, generates functional Tregs and provides a system to elucidate the mechanism of Treg development.

Potential for clinical ex vivo expansion of cord blood haemopoietic stem cells using non-haemopoietic factor supplements.

The establishment of culture systems that promote haemopoietic stem cell (HSC) self-renewal and expansion ex vivo will increase the clinical potential of umbilical cord blood (CB) HSC transplantation. Studies defining key signalling pathways that regulate development and expansion of HSC in vivo have greatly facilitated development of protocols for expanding HSC in ex vivo culture. Recently a number of soluble factors with novel stem cell expansion activity have been identified as part of pathways associated with mesodermal induction, or as factors produced by supportive stroma. These have been reported to support, to varying degrees, HSC self-renewal under in vitro conditions. Here we review the activities of these new factors and consider their future potential as components in ex vivo expansion culture for CB HSC. Finally we discuss the challenges associated with applying these factors to clinically relevant culture systems.